Steroid production



United States Patent S'IER'OID PRODUCTION Philip F. Beal HI, Kalamazoo, and John A. Hogg, Portage Township, Kalamazoo County, Mich., assignors to 'Ihe Upjohn Company, Kalamazoo, Mich., a corporation of Michigan No Drawing. Application June 2, 1954, Serial No. 434,071

8 (Ilaims. (Cl. 260-23955) This invention relates to a novel process for the production of B-cyclic ketals of alkyl 3-keto-l1B-hydroxy- 4,17 (20 -pregnadiene-21-oate.

It is an object of the present invention to provide a novel process for the production of a 3-cyclic ketal of alkyl 3 keto 115 hydroxy 4,17(20) pregnadiene- 21-oate. Another object is the provision of a process for the conversion of a B-cyclic ketal of alkyl 3,11-diketo- 4,17(20)-pregnadiene-2l-oate into a 3-cyclic ketal of 1 15,21-dihydroxy-4,17(20)-pregnadiene-3-one. Still another object is the provision of a process for the conversion of alkyl 3,11-diketo-4,17(20)-pregnadiene-21oate into 11 3,21 dihydroxy 4,17(20) pregnadiene 3 one. Other objects Will be apparent to those skilled in the art to which this invention pertains.

The conversion of alkyl 3,11-diketo-4,17(20)-pregnadiene-Zl-oate to 11 8,21-dihydroXy-4,17(20)-pregnadiene- 3-one by reactions involving the process or" the present invention may be represented by the following formulae:

O i|iO-A1kyl CH I (OHg),.O 0

OHzOH AB IV LiAlH; (CH2) -0 4 (CHi)n-0 GHO l H-() CHzOH tn 1 2,758,993 Patented Aug. 14, 1956 wherein R is hydrogen or a lower-alkyl radical and n is the integer one or two.

According to the present invention, a 3cyclic ketal of alkyl 3,11-diketo-4,17(20)-pregnadiene-21-oate (H) as defined herein is reduced with sodium borohydride to produce the corresponding 3-cyclic ketal of alkyl 3-keto- 11,8-hydroXy-4,17(20)-pregnadiene-21-oate (III). The

. thus-produced 3-cyclic ketal of alkyl 3-keto-11fi-hydroxyuct is the llfl-isomer, this production of lla-isomer is,

disadvantageous since it results in a corresponding reduction in yield of the luff-isomer. When a S-cyclic ketal of 11/3,21-dihydroxy-4,17(20)-pregnadiene-3-one (IV) is. produced by the method of the present invention, i. e.,. reducing the ll-keto group of the starting 3-cyc1ic ketal of alkyl 3,11-diketo-4,17(20)-pregnadiene-2l-oate (II) with sodium borohydride and the 21-acid ester group with. lithium aluminum hydride, no significant amount of the. Ila-hYdIOXY isomer is obtained, and the yield of hydroxy isomer is correspondingly higher. Since hydrocortisone is more readily prepared from the H S-isomer than the Ila-isomer, this increase in yield of the 115- isomer, when following the process of the present invention, is highly advantageous.

T e thus-produced ,S-cyclic ketal of 115,21-dihydroxy- 4,17(20)-pregnadiene-3-one (IV) is readily hydrolized under aqueous acid conditions to 1113,21 -.dihydroxy- 4,17'(20 pregnadiene 3 one (V). 11,6,21 dihydroxy-4,17.(Z)-pregnadiene-3-one can be converted to the physiologically active hydrocortisone acetate by acetylation of the 2l-hydroxy group followed by oxygenation of the thus-produced. llfi-hydroxy-2lacetoxy4,17(20)- pregnadiene-3-one with hydrogen peroxide and a small amount of osmium tetroxide in tertiary butyl alcohol, all as described more fully hereinafter.

The 3-cyclic ketal of alkyl 3,11diketo-4,l7(20)-.pregnadiene-3-one (II) is readily prepared by the reaction of alkyl 3,1l-diketo-4,1'7 (2Q)-pregnadiene-21-oate (I) with an alkane-LZ-di'ol or alkane-1,3-diol, preferably ethylene glycol, in the presence of an acid catalyst, under ketalizing conditions, for example, as described in Preparation 3. Alkyl 3,1l-diketo-4,'I7(20) pregnadiene-21-oate (I) can be prepared by reacting ll-ketoproges-terone with ethyl oxalate in the presence of a molar equivalent of sodium ethoxide, followed, in turn, by bromination with about two. molar equivalents of bromine and by reaction with a sodium a-lkoxide, ordinarily sodium methoxide or ethoxide, all as disclosed more fully in the preparations hereinafter.

In carrying out the process of the present invention, a 3-cyclic ketal of alkyl, 3,11-diketo-4,l7(20)-pregnadiene-2l-oate (II), usually dissolved in a suitable solvent, e. g., an hydrous or aqueous isopropanol, methanol, ethanol, dioxane, tetrahydrofuran, or the like, is mixed with sodium borohydride, usually in an aqueous solution stabilized with alkali. An excess of sodium borohydride over the amount theoretically required may be employed and is ordinarily preferred. The reaction temperature is ordinarily somewhat above room temperature, e. g., between about degrees Centigrade and. about fifty degrees centigrade, although temperatures between about zero degrees centigrade and about eighty degrees centigrade can be employed. Temperatures below about 35 degrees centigrade require fairly long reaction times to reach completion, whereas temperatures above about fifty degrees centigrade tend to cause decomposition of the sodium borohydride. Any excess sodium borohydride remaining at the end of the reaction can be decomposed Y with dilute acid or acetone.

The thus-produced 3-cyclic ketal of alkyl 3-keto-l 1,6- hydroxy-4,l7(20)-pregnadiene-2l-oate (Hi) can then be converted to a 3-cyclic ketal of 11/8-21-dihydroxy- 4,17(20)-pregnadiene-3-one (IV) by reduction with lithium aluminum hydride. The reduction-can be performed in diethyl ether, tetrahydrofuran, benzene, Skellysolve B hexane hydrocarbons, or mixture of these, ordinarily at a temperature between about room temperature and the boiling point of the reaction mixture.

A preferred aspect of the present invention involves starting with a 3-cyclic ketal of alkyl 3,1'1-diketo- 4,17(20)-pregnadiene-3-one and, without purification of the intermediate product, reducing the ll-keto group with sodium borohydride followed by reducing the 21 acid ester group with lithium aluminum hydride. The thus-reduced compound (IV) can then be hydrolyzed without purification to produce 11,6,21-dihydroxy- 4,1?(20)-pregnadiene-3-one (V). For example, the 3- ethylene glycol ketal, or like ketal, of alkyl 3,11-diketo- 4,17(20)-pregnadiene-21-oate (II) is preferably produced by the reaction of ethylene glycol or the like with an alkyl 3,11-diketo-4,l7(20)-pregnadiene-21-oate (I) and is then reacted with sodium borohydride without purification. The thus-produced 3-ketal of alkyl 3-keto-1 1phydroxy-4,17(20)-pregnadiene-21-oate (III) is then re duced with lithium aluminum hydride without isolation, to produce the 3-ketal of l1p,21-dihydroxy-4,17(20)- methylene chloride and pregnadiene-3-one (IV) which in turn can be hydrolyzed to produce 11B,2l-dihydroxy-4,17(20)-pregnadiene-3-one (V). A convenient means of accomplishing this involves formation of II in benzene, distilling the benzene and replacing it with ethanol, adding the sodium borohydride to produce III, extracting HI with ether and reacting it with an excess of lithium aluminum hydride, destroying the excess .lithium aluminum hydride with water, acetone or ethanol, etc., distilling the ether, replacing the ether with acetone, and then acidifying the aqueous acetone solution with hydrochloric acid and bydrolyzing IV to produce V.

The following preparations and examples are illustrative of the products and process of the present invention but are not to be construed as limiting.

PREPARATION 1.SoD1UM ENOLATE o1= 11-KETo-21- ETHOXYOXALYLPROGESTERONE To a mixture of 3.4 milliliters of a 3.4 N methanolic sodium methoxide solution, 0.45 milliliter of absolute ethanol, and twenty milliliters of dry benzene, said mixture previously having been distilled until eight milliliters of distillate had been collected and then cooled, was added 2.3 milliliters of ethyl oxalate and a solution of 3.28 grams of ll-ketoprogesterone in 38 milliliters of dry benzene. The solution became turbid and a yellow precipitate formed. The reaction mixture was stirred for ninety minutes, 55 milliliters of ether was then added thereto, and stirring was continued for sixty minutes, whereafter a -mi1liliter portion of ether was added thereto. The thus-formed yellow precipitate of the sodium enolate of 1l-keto-21-ethoxyoxalylprogesterone was filtered, washed with several fifty-milliliter portions of ether, and after drying found to weigh 3.65 grams. The ether wash contained 0.54 gram of unreacted ll-ketoprogesterone. The yield of the sodium enolate of 11- keto-Zl-ethoxyoxalylprogesterone was 81 percent of the theoretical or practically quantitative calculated on the reacted ll-ketoprogesterone. The presence of a sodium enolate was verified by the extreme solubility of the product in water and by a positive ferric chloride test for enols as exhibited by the formation of a bright red color when the product was dissolved in alcoholic and aqueous ferric chloride solutions.

PREPARATION 2.-METHYL 3 ,1 1 -DIKETO-4, 17(20)- PREGNADIENE-Zl-OATE To a stirred solution of 4.50 grams (0.01 mole of the sodium enolate of 11-keto-2l-ethoxyoxalylprogesterone and two grams of potassium acetate in milliliters of methanol was added clropwise 3.09 grams (1.00 mL; 0.0193 mole) of bromine. When the addition was complete, 3.24 grams (0.06 mole) of sodium methoxide in forty milliliters of methanol was added thereto, whereafter the whole was maintained at about 25 degrees centigrade for sixteen hours. The reaction mixture was then mixed with a large volume of water and the whole was extracted successively with one portion of benzene and two portions of methylene chloride. I The combined extracts were dried over anhydrous sodium sulfate and the solvent was then removed therefrom by distillation. The residue was dissolved in 100 milliliters of chromatographed over and eluted from 150 grams of Florisil synthetic magnesium silicate with methylene chloride containing increasing amounts of acetone. The methylene chloride plus five percent acetone eluates contained 1.2 grams of 3,11- diketo-4,l7(20)-pregnadiene-2l-oic acid methyl ester, melting at to 188 degrees centigrade. Crystallization of these crystals from a mixture of acetone plus Skellysolve B hexane hydrocarbons gave crystals melting at 207 to 212 degrees centigrade.

Similarly, other alkyl esters of 3,11 -diketo-4,17(20)- pregnadiene-Zl-oic acid such as, for example, the ethyl ester, the propyl, butyl, amyl, hexyl,- heptyl; octyl, or like ester, are prepared by reacting the sodium enolate of 1l-keto-Zl-ethoxyoxalylprogesterone with a sodium or potassium alkoxide wherein the alkyl group of the alkoxide is the same as the alkyl ester group of the desired steroid product.

PREPARATION 3.3-BTHYLENE GLYCOL KETAL or METHYL 3, 1 l-DIKETO-4, 17 (20)PREGNADIENE-2 l-oxra To a solution of 1.5 grams (0.0042 mole) of methyl 3,11-diketo-4,17 (20)-pregnadiene-21-oate dissolved in 150 milliliters of benzene was added 7.5 milliliters of ethylene glycol and 0.150 gram of parawtoluenesulfonic acid and the whole was then heated with stirring at the reflux temperature of the reaction mixture for 5.5 hours. The cooled reaction mixture was washed with 100 milliliters of a one percent aqueous sodium bicarbonate solution. The benzene layer was then poured on a column of 150 grams of Florisil synthetic magnesium silicate. The column was developed with 100-milli1iter portions of solvents of the following composition and order: eight portions of methylene chloride and three portions of methylene chloride plus four percent acetone. The methylene chloride eluates contained 1.08 grams of the 3-ethylene glycol ketal of methyl 3,11- diketo-4,l7(20)-pregnadiene-2l-oate, which upon recrystallization from a mixture of ethyl acetate and Skellysolve B hexane hydrocarbons melted at 188 to 190 degrees centigrade and had the analysis given below. The methylene chloride plus four percent acetone eluates contained 0.390 gram of pure starting methyl 3,11-diketo-4,17(20)-pregnadiene-21-oate. The yield of product was 87 percent of the theoretical calculated on the amount of starting steroid which reacted.

Analysis.Calculated for C24H32052 C, 71.94; H, 8.05. Found: C, 71.90; H, 7.95.

Similarly, the 3-ethylene glycol ketals of other alkyl esters of 3,11-diketo-4,17(20)-pregnadiene-21-oic acid such as, for example, the ethyl ester, the propyl, butyl, amyl, hexyl, heptyl, octyl, or like esters, are prepared by reacting the selected alkyl ester of 3,11-diketo- 4,17 (20)-pregnadiene-2l-oic acid with ethylene glycol according to the method described in Preparation 3 in the presence of an acid catalyst such as, for example, anhydrous hydrogen chloride, benzenesulfonic acid, paratoluenesulfonic acid, or the like.

In the same manner as described above, reacting methyl 3,11-diketo-4, 17 (20) -pregnadiene-21-oate with trimethylene glycol in the presence of an acid catalyst is productive of the 3-trimethylene glycol ketal of methyl 3,11-diketo-4,17(20)-pregnadiene-2l-oate.

Similarly, other 3-ketals of this and other esters of 3,1l-diketo-4,l7(20)-pregnadiene-21-oic acid are produced by the reaction of the selected ester of the abovedescribed steroid acid, especially the methyl, ethyl, propyl, butyl, amyl, hexyl, heptyl, or octyl ester, with a glycol such as, for example, ethylene glycol, propylene glycol, trimethylene glycol, an alkyl substituted ethylene glycol, propylene glycol, or trimethylene glycol, or the like, in the presence of an acid catalyst, such as, for example, para-toluenesulfonic acid, hydrogen chloride, sulfuric acid, or the like.

Example 1.3-ethylene glycol ketal of methyl 3-ket0- 11fi-hydr0xy-4J 7 (2 0) -pregnad lens-21 -0ate A mixture of five grams (0.014 mole) of methyl 3,11- diketo-4,17(20)-pregnadiene-21-oate, twenty milliliters of ethylene glycol and 0.3 gram of para-toluenesulfonic acid in 150 milliliters of benzene was refluxed with vigorous stirring for five hours. The mixture was cooled and washed with twenty milliliters of a saturated aqueous solution of sodium bicarbonate and then with water. The sodium bicarbonate and aqueous washes were extracted with benzene which was added to the washed benzene. The combined benzene solutions were dried with sodium sulfate and the benzene distilled therefrom to leave a residue consisting essentially of the 3-ethy1- ene glycol ketal of methyl 3,11-diketo-4,17(20)-pregnadiene-Zl-oate.

The thus-produced 3-ethylene glycol ketal of methyl 3,1l-diketo-4,l7(20)-pregnadiene-2l-oate was dissolved in milliliters of isopropyl alcohol and a solution of two grams of sodium borohydride in twenty milliliters of an 0.1 N solution of aqueous sodium hydroxide was add-. ed thereto. The solution was stirred for four days at 37 degrees centigrade, at the end of which time no sodium borohydride remained. The isopropyl alcohol was distilled at reduced pressure and the residue extracted with two -milliliter portions of benzene which were combined and reduced in volume to about one-half by distillation at reduced pressure. The resulting benzene solution was chromatographed over 300 grams of Florisil synthetic magnesium silicate with Skellysolve B hexane hydrocarbons containing increasing amounts of acetone. The eluate fractions consisting of Skellysolve B plus five percent acetone contained 4.25 grams, a yield of 85 percent of the theoretical, of the 3-ethylene glycol ketal of methyl 3-keto-1 15-hydroxy-4, 17 20 -pregnadiene-2l-oate which, after recrystallization from ethyl acetate, melted at 167 to 169 degrees centigrade and had the analysis given below.

Analysis.Calculated for C24H34O5: C, 71.61; H, 8.51. Found: C, 71.65; H, 8.78.

Similarly, other 3-cyclic ketals of alkyl 3-keto-1lfihydroxy-4,17(20)-pregnadiene-21-oates are prepared by reaction of sodium borohydride with a 3-cyclic ketal of an alkyl 3,11-diketo-4,17(20)-pregnadiene-2l-oate, especially those described in Preparation 3, wherein the cyclic ketal group and alkyl ester group correspond to the desired cyclic ketal group and an alkyl ester group of the reaction product. Starting steroids for this reaction include 3-cyclic ketals of alkyl 3,11-diketo-4,17(20) pregnadiene-Zl-oates wherein the cyclic ketal group is, for example, the ethylene glycol ketal, the propylene or trimethylene glycol ketal, or the cyclic ketals derived from butane-1,2-diol, butane-1,3-diol, butane-2,3-diol, pentane-1,2-diol, hexane-1,2-diol, heptane-1,2-diol, octane-1,2-diol, and others, and wherein the alkyl group is, for example, methyl, ethyl, propyl, isopropyl, amyl, isoamyl, sec-amyl, hexyl, heptyl, octyl and the like.

Example 2.3-ethylene glycol ketal 0) 116,21-dihydr0xy- 4,1 7 (2O -pregnadiene-3-0ne A solution of 1.62 grams of the 3-ethylene glycol ketal of methyl 3-keto-11,8-hydroxy-4,17(20)-pregnadiene-21- oate, prepared in the manner described in Example 1, in seventy milliliters of benzene was added dropwise to a stirred mixture of 1.50 grams of lithium aluminum hydride and fifty milliliters of anhydrous ether. When addition was complete, the reaction mixture was refluxed for one-half hour whereafter the mixture was cooled to room temperature. Fifty milliliters of water was then cautiously added to the stirred reaction mixture to decompose the excess lithium aluminum hydride, followed by 200 milliliters of methylene chloride. The whole was then centrifuged to facilitate separation of the organic and aqueous phases. The organic phase was separated, the solvent distilled and the white crystalline distillation residue was crystallized from a mixture of ethyl acetate and Skellysolve B hexane hydrocarbons to yield crystalline 3-ethylene glycol ketal of 11B,21-dihydroxy-4,17(20)- pregnadiene-3-one in two crops. The first crop, the analysis of which is given below, melted at 191 to 194 degrees centigrade and the second at 172 to degrees centigrade.

Analysis.Calculated for C23H34O4: C, 73.76; H, 9.15. Found: C, 73.87; H, 9.22.

In the same manner as described above, the 3-propylene glycol ketal of 1lfl,2l-dihydroxy-4,17(20)-pregnadiene-S-one is prepared by reacting with lithium aluminum hydride in ether the 3-propylene glycol ketal of an alkyl ester of 3-keto-1lp-hydroxy-4,17(20)-pregnadiene- 21-oic acid, prepared as given in Example 1.

similarly, other 3 iot'a1s of 1lB,2'1-dihydroxy 4;17120) pt ad qn a e P par x st g. sthrfi ke f. l .s h hidt i tuizort r ei tt ezlh, e, h et y proi ylii pr py my thit erl, aptyl, or dctyl ester of 3-1"ethyli1e glycol ketal of 3- k 'i 'T- fl5 Y QXi AJ7Q i snz d lr s .i q th 355553618 12? glyeol, propane-.ot-diol; butaIieELZ diOl, butaiief-lj 'diol, pentane-ll-diol, pentaiie-lii} ol hexane- 1 ,2 dio'l,. hep tane-h-ydiol, octan l,2 di'ol or like i cyclic ketal 'of ,itiet yl 3- kto"- 11,6{hydroxy 4,17(20) pregnadieriie Zl oate, with lithium aliiriiinilmhydride in ether, dioxane, ttral'iydrofui'an, or other suitable solvent.

Example 3 1 1 19,21 -di}iydr0xy-4 ,1 7(20)-pfegnadieneoiro' gram or the s jethyktieglyeol ktl of methyl 3- l 5 tiy'dioiy-4, 17120;) p i'gn adiene 2 l-bate, pre ared atc'cordiii'g to the method described in Example 1, but not purified, was dissblved milliliters of benzene and 0.2 gra n or lithium aliuiiinum hydride dissolved in 25 milliliters of absolute ether was slowly added The resulting mixture was stirred for about eighteen hours and then decomposed by the addition of water. The decomposed mixture was filtere'd, the filter cake bein washed thorou hly with ethyl acetate and ether. The filtrate was evaporiit'e'dhnd the residue dissolved in forty milliliters of a'cletdiiep To this solution was dde'd ten rnilliliters of water and eight drops of cjo ated sulfuric acid and the mixture allowed to stand f i abou eighteen lio'u'rs, Thesolutiofi was neut r itlized th sodium bicarbonate the then evap rated at robrii temperature. The reaction productwas separated frornthe inorgaiiic salts b'y extractioii with ethyl acetate which was then evaporated. The residue wa's recrystalliz'ed ttotti a ihiiti ie or ethyl acetate and skeu sowe .13 Hex 'nf hydrocarbons to give a fiist i' p (if 440 millir ms. d. 5 oem. tti the e i. f. 1 15,2l diliydrbxy 4,17( pregiititlirie 3one, irieltih at 18; to 186' degrees centig'rade and a s'ecoiid crop of 160 riiilligia t 1 altern procedilre or the hydrolysis step involv iii-g" the ,hya lysis hrv the isolated 3 et ylerie glycol of llp,21 dihydroxy 4,17(20'j-prenadine-3 ohe is shown below.

A solution of 0.572 grath 0.0015 mole of the 3-ethll? XQQ k i fi l !???lz i d y-f 7(20)-pre nadiene i -onfe in fo'rtymilliliters oi acetone was diluted with water-to a volume of fifty milliliters an'd eight drops of concentrated sulfuric acid was then added thereto,

whereafter the reaction mixture was kept at room tempelra ture for 24 hours. The reaction mixture was then made alkaline by the addition of a saturated aqueous sodium bicarbonate solution and the acetonewas then evaporated from the mixture. Methylene chloride and more water were then added, the methylene chloride layer removed; and the solvent distilled therefrom. The resi-. due, after drying in vacuo, consisted .of the theoretical 0.518 gram of 115.2l-dihydroxyl,17(20)-pregnadiene-3 In the same manner as described in Example 3, 115,21- dihydroxy- 4,17(2,0) -pregnadiene 3-oiie is prepared by contacting other 3-kctals of 1lB,21 dihydroxy-4;17(20)- preghadiene-3-oi1e, especiallyth 3-lietals described in the preparations and examples hereinbefore; with a hydrolyzing ag'e'nt such as, for example, dilute hydrochloric acid, sulfuric acid, or the lik'e'.

The conversion of 115,21-dihydroxy 4,17(20 apt-egna'din-3-oii into" the physiologically active hydrocortisone acetone is shown below.

1 IB-FiydrOky-ZI-acet0xy 4,17(Z0) -pregnadi'ene-3-one A sol tion (5130.518 g'jra rii f 11 21 d'hydro'iy 4,l7( 20) pfegiiadiene-Z-o ein live in 'lllters of pyridine was with two r'riilli erg of a'ctie afihyd'ride and the whole; Was then maintaihtl at room temperature for seventeh The eluate fractions containing ten perceiit andfiften percent acetone, respectively, were combiiied, the solvent removed therefrom, and the crystalline residue was crystallized from a mixture of ethyl acetate and Skelly! solve B to yield as the first crop. 0.253 gram, a yieldof 45v percent of thethe'oretical, of llfi-hydroxy 2laetoxy- 4,l7(20)-pregnadiene-3-one melting at 183 to 186 degrees Centigrade. i

Artalysis.-Calculated for. C2 H32O4L. C, 74.16; H, 8.66. Found: C, 74.18; H, 8.45; C, 73.95; H, 8.74. 11B,I7&2]-trihydroxy fjii egitiiflbfi Keit'dalis C'oht To a stirred suspension of 0.124 (0:00033 mole) of 115 hydroxy 21 acetoxy 4,17(20 preg iiadine 3-one in two milliliters of tertiary butyl alcohol was added 0.26 milliliter of a 2.6 molar solution .of hyd'rdn peroxide. in tertiary alcohol and 0.30 milliliter of a solutionof 1.00 gram of osmium tetroxide in milliliters of tertiary butyl alcohol. An additional 0.50 milliliter Of the above-described osmium tetroxide solution was added to the reaction mixtilre dining the next thirty hoil'rs. After the first four hours of reaction time the reaction mixture darkened and becaihe homogeneous. The reaction mixture was stirred and maintained at tooth temperature for an additional 84 hours, whrealft'r water i and inetliylene chlotidewere added thereto. The whole was distilled at reduced pressure to remove the organic solvents and the product was extracted from the residue with methylene chloride; whreafter the extract was freed of solvent by evaporation. The residue, after dissolving in a mixture ofv five milliliters of methanol and one milliliter of a solution or 030 gram or sodiuifi sulfite in five milliliters of water, was heated on a steam bath fo r thirty minutes. The t11,8,17,21=dihydroXy-4-preg1iene- 3,20-dione was separated therefrom by extraction with tr'ieth lene chloride, which was thereafter retrieved b distillation iii vacuo; The 0.101 gram of residue cohsisted of about fifty percent of the desired 115375521- trihydroxy-4-pregriene-3,ztl dione (K'ndlls Compound F). It is to be understood that this invention is not to be limited to the exact details of o eration or exact cornpounds shown and described as obvious modifications ar'id eqiliva'lehts will be apparent to o e skilled in the art arid the invention is therefore to be limited dilly by the scope of the appended claims.

1. The process which comprises; reducing; with sodium borohydride a 3- cyclic lie tal of alkyl 3 ,1 1-dil eto 4,17 (2Q) pregnadieneQl-oate represented by the following formula:

(c arli -o 9 wherein R is selected from the group consisting of hydrogen and lower-alkyl groups and n is an integer from one to two, to produce the corresponding 3-cyclic ketal of alkyl 3-keto-11fl-hydroxy- 4,l7(20) pregnadiene-Zloate.

2. The process of claim 1 wherein R is hydrogen and n is the integer one.

3. The process of claim 1 wherein R is hydrogen and n is the integer two.

4. The process of claim 1 wherein R is hydrogen, n is the integer one and the alkyl group is methyl.

5. The process of claim 1 wherein R is hydrogen, :1 is the integer one, the alkyl group is methyl, the reaction solvent is an aqueous alkali containing lower-alkanol and the reaction temperature is between about 35 and about fifty degrees centigrade.

6. The process which comprises the steps of (1) reducing with sodium borohydride a 3-cyclic ketal of alkyl 3,1l-diketo 4,17(20) pregnadiene-Zl-oate represented wherein R is selected from the group consisting of hydrogen and lower-alkyl groups and n is an integer from one to two, to produce the corresponding 3-cyclic ketal or" alkyl 3-keto-llfl-hydroxy- 4,l7(20) pregnadiene-Zloate, and (2) reducing the thus-produced 3-cyc1ic ketal of alkyl 3-keto-1 lfl-hydroxy 4,l7(20) pregnadiene-21- oate with lithium aluminum hydride to produce the corresponding 3-cyclic ketal of 11fi,2l-dihydroxy-4,l7(20)- pregnadiene-B-one.

7. The process of claim 6 wherein R is hydrogen and n is the integer one.

8. The process of claim 6 wherein R is hydrogen, n is the integer one and the alkyl group is methyl.

References Cited in the file of this patent UNITED STATES PATENTS 2,622,081 Bernstein Dec. 16, 1952 2,623,885 Miescher Dec. 30, 1952 2,646,434 Bernstein July 21, 1953 2,671,095 Levin Mar. 2, 1954 2,674,606 Levin Apr. 6, 1954 

1. THE PROCESS WHICH COMPRISES: REDUCING WITH SODIUM BOROHYDRIDE A 3-CYCLIC KETAL OF ALKYL 3,11-DIKETO-4,17(20)PREGNADIENE-21-OATE PRESENTED BY THE FOLLOWING FORMULA: 